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The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability

The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability


Title: The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability
Author: Arason, Adalgeir   orcid.org/0000-0003-0480-886X
Agnarsson, Bjarni A.
Jóhannesdóttir, Gudrún
Jóhannsson, Óskar Th
Hilmarsdóttir, Bylgja
Reynisdóttir, Inga
Barkardottir, Rosa Bjork   orcid.org/0000-0003-0629-2772
Date: 2019-11-01
Language: English
Scope: 882
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Biomedical Center (UI)
Lífvísindasetur (HÍ)
Series: Genes;10(11)
ISSN: 2073-4425
DOI: 10.3390/genes10110882
Subject: BRCA1; Breast cancer; Cancer risk; Homozygous lethality; Knudson's two-hit model; LOH; Ovarian cancer; Tumorigenesis; VUS; Gen; Brjóstakrabbamein; Eggjastokkar; Erfðafræði
URI: https://hdl.handle.net/20.500.11815/1609

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Citation:

Arason, A., Agnarsson, B. A., Johannesdottir, G., Johannsson, O. T., Hilmarsdottir, B., Reynisdottir, I., & Barkardottir, R. B. (2019). The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability. 10(11), 882.

Abstract:

Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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